Therapeutic method to reduce pain and inflammation

ABSTRACT

Method of treating veterinary or human patients for relief of dermal or sub-dermal pain and inflammation by topical application of a therapeutic agent comprising propylene carbonate.

This is a continuation-in-part of U.S. patent application Ser. No. 439,620, filed Nov. 5, 1982, now abandoned.

BACKGROUND OF THE INVENTION

This invention pertains to a new method for treating pain, inflammation, trauma, allergy, and disease by the topical application of a therapeutic agent having previously unrecognized analgesic, anti-allergenic, and anti-inflammatory properties, or by the topical application of the same agent in combination with a second therapeutic agent, the effectiveness of which is enhanced by the first agent.

As stated in the publication of Texaco Chemical Company entitled "Ethylene Carbonate-Propylene Carbonate," "Propylene Carbonate is a clear, mobile, practically odorless liquid." It is 4-methyl 2-dioxolone, a cyclic organic ester which is a known solvent for a variety of polar and non-polar organic compounds and for many inorganic chemical and biological materials. Its chemical properties include low toxicity. The same publication further indicates that propylene carbonate is an excellent additive for certain clays and gel bases useful in cosmetic and personal care products. Still further, the publication refers to acute toxicity tests which indicate that propylene carbonate is practically non-toxic and is otherwise indicated to be non-offensive in subchronic dermal applications, skin sensitization tests and inhalation tests, though temporarily offensive to a minor degree to the eyes.

The Texaco publication also includes a extensive bibliography, including an applications section entitled "Cosmetics and Personal Care," in which four patent references and three literature references are noted.

No indication whatsoever is found in the above-referenced Texaco publication to suggest, in any way, the possible utility of propylene carbonate as a therapeutic agent for treating pain, inflammation, trauma, allergy, or disease.

A search has been conducted in the U.S. Patent and Trademark Office to identify references relating to or disclosing the use of propylene carbonate for essentially any pharmaceutical purpose. Patents identified in this search were:

    ______________________________________                                         U.S. PAT. NO.     INVENTOR                                                     ______________________________________                                         4,017,615         Shastri, et al.                                              4,279,901         Ronald M. Kudla                                              3,924,004         Chang et al.                                                 4,273,770         Francisco Alvarez                                            4,242,334         Stache et al.                                                3,829,826         Gaetano D'Alelio                                             3,574,118         Wayne Otto Baker                                             3,362,927         Edwin H. Lochridge                                           3,185,627         Gus S. Kass                                                  3,178,352         Roy Erickson                                                 3,136,696         Benjamin Harrison                                            3,472,931         R. B. Stoughton                                              4,244,942         Kamishita et al.                                             3,298,919         Jack L. Bishop, Jr.                                          3,352,753         Leonard J. Lerner                                            ______________________________________                                    

The first three of the above-listed patents are listed in the Application-Cosmetics and Personal Care subsection of the bibliography in the above-referenced Texaco Chemical Company publication (page 24). The primary focus of Kudla is on ethylene carbonate rather than propylene carbonate. It will also be noted that the remaining references in that bibliography subsection all deal only with hair-treatment preparations. The patents on Chang, Shastri et al., and Kudla all relate to topical ointment compositions in which, generally, propylene carbonate or ethylene carbonate is combined with co-solvents or with other constituents, such that only a minor proportion of propylene carbonate is included in each composition, generally less than 40% in Chang and 30% in Shastri, for example. The compositions, in which propylene carbonate is incorporated in accordance with the teachings of these patents, each include specific therapeutic agents, such as anti-biotics, steroids, antihistamines, antiseptics, anesthetics, and corticosteroids.

The D'Alelio patent relates to the use of propylene carbonate in removing dental calculus, relying on its non-toxic solvent function for swelling the organic binder phase of the calculus.

Alvarez is directed to novel anti-inflammatory agents. It indicates, however, that such agents may be combined with a "pharmaceutically acceptable solvent," among particularly suitable examples of which is listed propylene carbonate. As in other applications of this type, the carbonate is generally carried in a semi-solid emulsion of oil and water, or water in oil including, for example, white petrolatum.

The Stache patent was cited apparently for its teaching of various carbonate-containing steroids useful in veterinary and human therapy. Notably absent, according to Applicants' reading of this patent, is any suggestion of the use of propylene carbonate in any manner different than that suggested in the other prior art references, cited above.

In addition to the foregoing, Applicants are aware of certain unpublished non-clinical work of others. Applicants' limited knowledge of this work prior to the present invention, indicated that propylene carbonate had been considered only for possible use as a rapid surface skin-penetrating carrier for a topically applied composition, namely suntan lotion, the objective of which was to eliminate the greasy surface feel commonly associated with existing suntan lotion. It is not known whether any such suntan lotion was ever prepared.

Notwithstanding prior knowledge of propylene carbonate and its limited use as a vehicle in topical medicaments, and notwithstanding the unpublished work of others suggesting propylene carbonate as a vehicle for suntan lotion, there remains a continuing need for more effective methods of therapy to relieve pain and inflammation and to treat trauma, allergy, and disease. This need has not been addressed in the art pertaining to propylene carbonate.

It is, therefore, the general object of the present invention to provide such a method by the topical application of a hitherto unrecognized therapeutic agent, either alone or in combination with a second agent, the therapeutic effectiveness of which is enhanced by the first agent.

BRIEF DESCRIPTION OF THE INVENTION

The present invention comprises a method to reduce pain and inflammation in surface tissue and in deep or sub-dermal tissue, such as bone, muscle, ligaments, or joints, of a human or veterinary patient by topical application, in the patient's skin or mucous membrane proximate the pain or inflammation, of a therapeutically effective amount of a medicament comprising propylene carbonate. The present invention also comprises a method to treat trauma, allergy or disease by the topical application of propylene carbonate, in combination with a second therapeutic agent appropriate to the trauma or allergy or disease, the effectiveness of which is enhanced by the propylene carbonate.

DETAILED DESCRIPTION OF INVENTION

As contrasted with prior art compositions in which limited amounts of propylene carbonate have been used as a vehicle or carrier for other pharmaceutical agents, the present invention involves a therapeutic method in which propylene carbonate is not merely a vehicle but a primary medicament. While the therapeutic composition used in the method of this invention may include other constituents, either as a stabilizer for the propylene carbonate or as a co-reactive medicament, the present invention has been found effective even in the absence of such stabilizers and co-reactive medicaments.

Thus, in most of the clinical tests described below, the effective therapeutical agent consisted essentially or entirely of propylene carbonate. These tests clearly demonstrate the hitherto unrecognized effectiveness of propylene carbonate as a therapeutic agent. Certain of the tests described below also demonstrate the effectiveness of propylene carbonate as a potentiating agent for a second or co-reactive medicament.

Technical explanations for the surprising results in the clinical tests of the present invention described below are speculative. Accordingly, Applicants do not wish to be bound by any such explanations. However, certain unique characteristics of propylene carbonate seem to be particularly significant.

First, the solvent properties of propylene carbonate are well known. Because of these properties, it has been used or proposed as a vehicle or carrier in a number of topically applied medicinal and cosmetic compositions. These same solvent properties, however, apparently based on the chemical affinity of propylene carbonate for a wide range of other chemical compounds, also make it appropriate as a penetrant. But enhanced penetrating properties due to the propylene carbonate constituent has not been a recognized characteristic of known propylene carbonate-containing medicinal and cosmetic compositions. Applicants now surmise this is because all such compositions include oils, fats, or emulsifiers, in addition to the propylene carbonate. These oils, fats, and emulsifiers are thought to inhibit the penetrating ability and mobility of propylene carbonate. In this respect, the "Comparative Example" discussed below is of interest.

As presently understood then, an important factor in the present invention is the absence, in the topically applied medicament used in this invention, of any penetration inhibiting constituent. This is believed to be important because it apparently enables the propylene carbonate, with its penetrating ability uninhibited, to migrate quickly to the sub-dermal region where its therapeutic value, and/or the therapeutic value of any co-reactive medicament with which it is combined, is expeditiously realized.

A second important characteristic of propylene carbonate, for purposes of the present invention, is thought to be the biological/chemical process by which it degrades through one or more free radical stages to non-toxic final products, namely propylene glycol and carbon dioxide. This may be of significance for two reasons. Primarily, if the final degradation products are innocuous, adverse long range side effects, caused by accumulated by-products, are unlikely. Secondly, the free radical intermediate products, through which propylene carbonate apparently degrades in the body, may function as metabolic accelerators and as nerve cell transmission blockers, resulting respectively in the enhancement of other normal bodily functions dependent on metabolic reactions and in the inhibition of neuro transmission of pain impulses to the brain. The latter may provide symptomatic relief of pain while the former may enhance the normal physiological tendency of a body member to counteract the abnormality, whether it be allergy, inflammation, trauma, or disease.

The accelerated metabolic activity associated with propylene carbonate degradation in the body may also be responsible for the enhanced effectiveness of other co-reactive medications administered in combination with propylene carbonate. For example, the clinical tests described below include several cases in which a solution of propylene carbonate with a co-reactive agent (namely aspirin, iodine, and penicillin, respectively, in separate tests) was used. Positive clinical therapeutic results were obtained in each case. The effectiveness of all three of these medications was apparently enhanced by the presence of propylene carbonate. The apparently improved pharmacologic responses suggest that only a reduced dosage of each medication would be needed in order to produce the desired therapeutic effect. An especially striking example was the case in which a solution of propylene carbonate and penicillin was applied locally to an abcessed tooth and gum (Test 73, below).

In Table I, below, are listed a number of clinical tests in which propylene carbonate was used alone, and in which almost immediate relief from pain, swelling, inflammation, and allergic phenomenon was obtained. Relief from pain usually lasted from 4 to 6 hours which coincides in general with the period of time believed to be required for the degradation of propylene carbonate in the body. In some of the clinical examples, repeated applications of propylene carbonate were necessary in order to obtain relief from pain; in others, prolonged relief was provided after only one application; in still others, continued use of propylene carbonate resulted in prolonged relief as more specifically indicated below. At least, temporary relief from pain, and at best, prolonged remission was obtained by the topical application of propylene carbonate alone. This was especially so in instances where pain and inflammation were associated with joint and muscle trauma, osteoarthritis, bursitis, tendonitis, sprains, hematomas, fractures, torn ligaments and muscles. In those instances where pain returned (although generally lessened) within 4 to 6 hours, repeated application of propylene carbonate seemed to hasten ultimate complete recovery.

                                      TABLE I                                      __________________________________________________________________________     Test                                                                           Patient                                                                             Grade & Date              Area of Topical                                                                          Time to    Duration                   Number                                                                              of Result                                                                              Age                                                                               Sex                                                                               Ailment     Application                                                                              Relieve Pain                                                                              of Effect                  __________________________________________________________________________      1.  E - 5/18/82                                                                            56 F  Bursitis    Left Shoulder                                                                            2-3 Min.   8-10 Hours                                    (Chronic) (mild)                                             2.  G - 3 Applica-                                                                         24 M  Lower Back Pain                                                                            Lumbar & Sacral                                                                          20-25 Min. 6-8 Hours                       tions 5/22/82 (3 Week Duration)                                                                          Regions                                              5/29/80 6/5/82                                                             3.  E - 3 Applica-                                                                         22 M  Infected Tooth                                                                             Skin Over Left                                                                           2-3 Min. Pain                                                                             6-8 Hours                       tions 5/22/82 and Jaw     Mandibular                                                                               & Swelling Re-                             5/23/82 5/25/82           Region    duced by 2nd                                                                   Application                            4.  E - 3 Applica-                                                                         67 M  Osteo-Arthritis                                                                            Hands & Shoulder                                                                         5 Min.     4-6 Hours                       tions 5/18/82                                                                  5/20/82 5/25/82                                                            5.  E - 4 Applica-                                                                         61 F  Osteo-Arthritis                                                                            Hands & Feet                                                                             3 Min.     4-6 Hours                       tions 5/25/82                                                                  5/26/82 5/27/82                                                                5/28/82                                                                    6.  F - 6/7/82                                                                             18 F  Pulled Groin                                                                               Left & Right                                                                             5 Min. -   30 Min.                                                   Inguinal Region                                                                          Slight Effect                                                                  Vague Response                         7.  E - 6/12/82                                                                            45 F  Foot Bones Broken                                                                          Ventrum & Dorsum                                                                         Immediate Ef-                                                                             30 Min.                                       Hematoma Right                                                                             of Foot   fect - Com-                                              Foot                  plete Relief                                                                   From Pain                              8.  E - 2 Applica-                                                                         43 M  Smashed Index                                                                              Index Right                                                                              3-5 Min. Pain                                                                             6-8 Hours                       tions 6/16/82 -                                                                              Finger (Nail bed)                                                                          Finger    Reduced; Moved                             AM and PM                           Finger Freely                                                                  With No Pain;                                                                  Healing Hastened                       9.  G - 6/16/82                                                                            16 F  Osteo-Arthritis -                                                                          Middle Finger                                                                            Two Appli-                                               Locked Middle         cations Need-                                            Finger                ed; Finger Un-                                                                 locked                                10.  E - 3 Applica-                                                                         31 F  Abcess Following                                                                           Skin Over Right                                                                          5 Min. - Pain                                                                             6 Hours                         tions 6/19/82 Tooth Removal                                                                              Mandible  Relieved                                   6/20/82 6/21/82                                                                              Healing Hastened                                            11.  N - 6/22/82                                                                            30 F  Sprained Wrist                                                                             Wrist     Little or No Effect;                                                           No Explanation Found;                                                          Possibly Psychosomatic Symptoms       12.  E - 4 Applica-                                                                         38 F  Osteo-Arthritis                                                                            Both Knees                                                                               Within 10  10-12 Hours                     tions 6/24/82 of Knees              Min. Pain Gone                                                                            Used as Needed                  6/25/82 6/26/82                                for 2 mo. Period                6/27/82                                        With Continued                                                                 Relief                     13.  E - 2 Applica-                                                                         74 F  Cervical Osteo-                                                                            Cervical Neck                                                                            30 Min.    8 Hours                         tions 6/18/82 Arthritis                                                        AM & PM                                                                   14.  E - 6/22/82                                                                            20 F  Sprained Left                                                                              Left Ankle                                                                               2-3 Min.   8-10 Hours                                    Ankle                                                       15.  G - 2 Applica-                                                                         35 F  (2 Teeth) Right                                                                            Right Jaw Pain-                                                                          5 Min. Pain                                                                               8 Hours                         tions 6/24/82 Lower Jaw; Post                                                                            ful & Swollen                                                                            Relieved, also                                           Wisdom Tooth          Swelling Seem-                                           Extractions           ed Reduced                            16.  E - 6/24/82                                                                            67 M  Osteo-Arthritis                                                                            Toes of Left                                                                             2 Min.     6-8 Hours                                     of Toes     Foot                 or Better                  17.  E - 3 Applica-                                                                         63 F  Osteo-Arthritis                                                                            Left Thumb,                                                                              On Hand 4-5                                                                               8-12 Hours                      tions 6/28/82 Left Thumb & Hip                                                                           Hand, & Hip                                                                              Min. - On Hip                                                                             Stiffness                       6/29/82 6/30/82                     15-20 Min. Down, Mo-                                                                      bility Up.                                                                     After Use                                                                      for 1 Week                                                                     Hip Pain                                                                       Gone - no                                                                      reapplica-                                                                     tion needed                18.  G - 2 Applica-                                                                         59 M  Lower Back Muscle                                                                          Lower Back 2                                                                             2-3 Hours  12 Hours                        tions 7/4/82  Sprain      Appl.                                           19.  N 7/5/82                                                                               45 M  Lower Back Pain                                                                            Lower Back 2                                                                             1st Appl. No                                                                              2-3 Min.                                      Chronic Inter-                                                                             Appl.     effect. 2nd                                                                               Slight                                        mittent for 10        Appl. 4 Hours                                                                             Improve-                                      Years - No            Later      ment Only -                                   Diagnosis                        No Signifi-                                                                    cant Effect                20.  N - 3 Applica-                                                                         80 F  Osteo Chronic Back                                                                         (Reports are Uncertain) Leg Pain Remained            tions 7/8/82  & Legs - 3 Ruptured                                                                        the same. No measurable improvement                  7/9/82 7/10/82                                                                               Lumbar Discs                                                21.  E - 2 Applica-                                                                         35 F  Chronic Pain of                                                                            Lower Back                                                                               10-15 Min. 6-8 Hours                       tions 7/10/82 Severe Scoliosis                 Continued Use                   7/11/82       (Lumbar Region)                  for 6 Weeks, as                                                                Needed, Gave                                                                   Consistent Re-                                                                 lief                       22.  E - 2 Applica-                                                                         27 F  Acute Tendonitis                                                                           Right Wrist &                                                                            10 Min.    8 Hours                         tions 7/13/82 Right Hand  Forearm              Repeated                                                                       Applica-                                                                       tions. Ef-                                                                     fective                                                                        over the                                                                       next week.                 23.  E - 7/15/82                                                                            47 M  Bursitis Right                                                                             Wrist & Shoulder                                                                         1-2 Min.   5-6 Hours                                     Wrist Left                                                                     Shoulder                                                    24.  E - 7/15/82                                                                            61 F  Osteo-Arthritis                                                                            Left Knee &                                                                              5 Min.     5 Hours                                       Left Knee & Right                                                                          Right Ankle                                                        Ankle                                                       25.  E - 7/16/82                                                                            60 F  Osteo-Arthritis                                                                            Distal & Proximal                                                                        Stiffness Re-                                                                             4 Hours                                       Both Hands, Fingers                                                                        Dip & Pip duced 5 Min.;                                            Marked Deformity                                                                           Joints    also Tenderness                                          of Pip Joints         Reduced on her Only                                                            Tender Joint, Pip                                                              Left Small Finger                     26.  F - 7/19/82                                                                            24 F  Herneated I.V.                                                                             L.sub.1 -L.sub.5 Area                                                                    10-15 Min. 4 Hours                                       Disc (Lumbar) -       Pain in Back                                             Later Removed         & Muscle Gone -                                                                Radiated Pain                                                                  to Legs Un-                                                                    effected                              27.  E - 2 Applica-                                                                         56 F  Cervical Pain &                                                                            Cervical  Pain Gone in                                                                              Remainder                       tions 7/19/82 Stiffness in                                                                               1-8       5 Min. -   of Day                          7/20/82       Morning               Refer to                                                                       #33                                   28.  F - 7/19/82                                                                            24 M  Middle Toe, Right                                                                          Pip × 2                                                                            Some Numbing                                                                              For 1 Week                                    Foot - Arthritis      of Mild Pain.                                                                             Afterwards                                    of Undetermined       Had taken  Toe was Mobile                                Type                  Indocin that                                                                              at Joint Where                                                      A.M. - Test                                                                               it was Pre-                                                         Invalid    viously Fixed.             29.  G - 7/24/82                                                                            50 M  Lower Back  Lumbo-Sacral                                                                             Pain Relief                                                                               5-6 Hours                                     Lumbo-Sacral                                                                               Region    in 10 Min.                            30.  E - 7/28/82                                                                            86 F  Osteo-Arthritis                                                                            Knees (P.C.                                                                              Pain Relief                                                                               4 Hours                                       Knees       With Aspirin)                                                                            1/2 Hour                              31.  Lidex Ointment Compared with 100% Propylene Carbonate                     a.   N - Lidex                                                                              61 F  Osteo-Arthritis                                                                            Left Hand Lidex                                                                          No Reaction                                                                               100% P.C.                       6/19/82                                        Applied Over                                                                   Lidex -                                                                        Still No Reaction                                                              in Left Hand               b.   E - 100% P.C.             Right Hand                                                                               2-3 Min.   4-6 Hours                       6/19/82                   Propylene Carbon-                                                              ate Only                                        32.  N - 5/20/82                                                                            70 F  Osteo-Arthritis                                                                            Hands Several                                                                            No Effect  Discovered That                                           Appl.                Water had Con-                                                                 taminated P.C.             33.  N - 7/25/82                                                                            56 F  Cervical Pain &                                                                            *1st Appl. effect    4 Hours                                       Stiffness Same                                                                             Lasted Only 10 Min.                                                Pt. as #27  2nd Appl. 2-3 Min.                                                             for Effect With                                                                Fresh P.C.                                      34.  E - 7/30/82                                                                            63 F  Osteo-Arthritis                                                                            Applied P.R.N.                                                                           Less P.C. Needed                                         Hip, Knee & Ankle                                                                          for 6 wks.                                                                               and Quicker Response                                                           After Repeated Use                     *Note: Suspect first application failed due to contamination of propylene      carbonate.                                                                    35.  E - 7/30/82                                                                            38 F  Night Cramps                                                                               To Calves of                                                                             20 Min.    For the Night.                                in Legs (Calf)                                                                             Legs                 No Awakening                                                                   from Cramps                36.  N to F - 8/5/82                                                                        69 M  Rheumatoid Arthritis                                                                       Hands     P.C. - No Relief; Used 2 Times             8/13/82 P.C.  Hands, Hip, & Leg                                                                          Daily for 1 Week. P.C.A. -                           8/13/82                   After 2 Days - Less Stiff                            P.C.A.*                   Swelling Less, Mild Relief -                                                   No Significant Improvement                      37.  E - 8/13/82                                                                            27 F  T.sub.11 & T.sub.12                                                                        T.sub.11 & T.sub.12 &                                                                    10 Min. Relief                                                                            Back                                          Severe Sprain                                                                              Dermatome            Improved                                      Intercostal                      After One                                     Pain - Rear                      Application                                   to Front                                                    38.  E - 8/15/82                                                                            56 F  Lower Back Pain                                                                            Lower Back                                                                               20 Min. No Several                                       Sacrum                Pain       Applications                                                                   Over Period                                                                    of 2 Weeks;                                                                    Relief Each                                                                    Time                       39.  G - 8/23/82                                                                            16 M  Trauma to Right                                                                            Fracture of                                                                              10-20 Min.                                               Wrist & Forearm                                                                            Radius & Ulna                                                                            Swelling Down                                            Swollen & Pain-                                                                            Applied to Wrist                                                                         Pain Diminished on                                       ful         & Forearm Forearm. Wrist                                                                 Slightly Numbed                       40.  G - 9/3/82                                                                             59 M  Hematoma on Right                                                                          To Hematoma                                                                              Within 11/2                                                                               Swelling                                      Forearm Result of     Hour       Reduced,                                      Trauma                           Pain Diminished            41.  E - 9/15/82                                                                            16 M  Trauma Left Fore-                                                                          To Left Fore-                                                                            2-5 Min.   Pain Relieved;                                finger, Jammed                                                                             finger &             Swelling Re-                                  Swollen Finger &                                                                           Hand                 duced in with-                                Hand, Severe Pain                in 1/2 Hour.                                                                   Finger Freely                                                                  Movable With-                                                                  out Pain or                                                                    Limitation                                    Also Right Scapula                                                                         To Skin over                                                                             2-5 Min.   Pain Com-                                     & Trapezius Right                pletely Re-                                   Muscle Traumatized               lieved - Free-                                Echymosis & Hematoma             dom of Movement                                                                Without Pain               42.  E - 10/2/82                                                                            56 M  Tennis Elbow Right                                                                         To Right Elbow                                                                           3-5 Min.   Pain Relieved                                                                  for 4-5 Hours              43.  E - 10/11/82                                                                           56 F  Back Sprain To Lumbar-Sacral                                                                         10-20 Min. Pain Relieved                                             Region               Remainder of Day           44.  F - 10/16/82                                                                           44 M  T2-Rib Broken                                                                              To Fracture Area                                                                         Within 5 Min.                                                                             Effective 1/2                                 With Referred                                                                              and T2 Dermatome                                                                         the Referred                                                                              Hour                                          Pain                  Pain Was Absent                                                                Movement on Site                                                               of Fracture Pain                                                               Confined though                                                                Reduced                               45.  E - 10/17/82                                                                           67 M  Hemiplegia- To Painful Arm &                                                                         5-10 Min.  Relieves Pain 4-5                             Stroke, Pain                                                                               Leg                  Hrs. Used Daily                               in Arm & Leg                     for 6-8 Weeks              46.  E - 11/3/82                                                                            56 F  Bursitis Rt.                                                                               1 Application                                                                            5 Min.     No Pain No Limit-                             Shoulder    at Bedtime           ed Motion the                                                                  Next Morning               47.  E - 11/4/82                                                                            16 M  Knee Trauma Rt.                                                                            1 Application                                                                            10-15 Min. No Return of Pain                             Knee Football                                                                              to Rt. Knee                                                                              Pain Reduced                                                                              Or Swelling the                                                     Swelling Down                                                                             Next Day                   48.  E - 11/10/82                                                                           32 F  "Joggers" Knee                                                                             1 Application                                                                            Pain Diminish-                                                                            No Return of Pain                             Pain        to Affected Knee                                                                         ed in 2-3 Min.                                                                            the Next Day                                                        Absent After                                                                   1/2 Hour                              49.  E - 11/16/82                                                                           50 F  Sprained Ankle                                                                             1 Application                                                                            Pain Gone in                                                                              No Return That Day                            (Rt.)                 10-15 Min. Slightly Tender                                                     Swelling   Next Day. PC                                                        Reduced    Reapplied, No                                                                  Return of Pain                                                                 Rest of Day                50.  E - 11/22/82                                                                           54 F  Unremitting Pain                                                                           Applied to the                                                                           Within 10 Min.                                                                            No Return of                                  from Osteo-Arthritic                                                                       Knees     Pain Remitted                                                                             Pain Rest of                                  Knees for 31/2 yrs.              Day                        51.  E - 11/21/82                                                                           24 F  1 Yr. Ago Broken                                                                           Applied to Pain-                                                                         Swelling Re-                                                                              Pain Disappear-                 11/22/82      Ankle (left)                                                                               ful Ankle on 3                                                                           lieved in  ed for the                      11/23/82      Pinned, Chronic                                                                            Different Days                                                                           2-3 Min.   Entire Day on                                 Swelling & Pain                  Each of the 3                                 for 1 Yr.                        Days                       52.  G - 11/25/82                                                                           23 F  Trauma to Lt.                                                                              Lt. Small Toe                                                                            3-5 Min.   First Application -                           Small Toe. Swollen                                                                         2 Applications       Pain and Swelling                             Purple & Painful                                                                           3 Hrs. Apart         Reduced. After 3                                                               hrs., Some Swelling                                                            & Pain Returned.                                                               Second Application -                                                           Reduced Pain &                                                                 Swelling                   53.  E - 11/27/82                                                                           22 M  L3, L4, & L5                                                                               Left Side L3, L4,                                                                        15 Min. Pain                                                                              1 Hr. - Pain Gone,                            Torn Tendons Lt.                                                                           & L5, also Inser-                                                                        Diminished no Return of Pain or                          Lat. Dorsal MM                                                                             tions of Lt. Lat.    MM Spasm; Patient                             Torn Ligament.                                                                             Dorsal MM.           was Up and Around                             Bed-fast 3 Days                                             54.  E - 11/28/82                                                                           51 F  Post Oper. - 4 wks.                                                                        On Incisional                                                                            10 Min.    Pain Gone in 10                               Hysterectomy                                                                               Scar, Inguinal       Min. with Return                              Incision Pain on                                                                           Regions & Inner      in 8 hrs.; then Pain                          Incision & Bilateral                                                                       Thighs               was Greatly Reduced                           Inguinal Ligament &                                                            Inner Thighs                                                55.  E - 11/29                                                                              27 F  Fractured Lt.                                                                              Applied Directly                                                                         10 Min. Pain                                                                              Only Slight Tender-             through       Clavicle Painful                                                                           Over Swelling                                                                            Reduced    ness Remained Over              12/12/82      & Swollen. PC                    the Fracture; Pain                            used Several ×/day         Reduced More After                            for 2 wks.                       Each Application           56.  G - 12/7/82                                                                            59 M  Toothache   Gum Area Sur-        After 3rd.                                                                     Application                                   Throbbing   rounding Tooth       in a Period of 2                                                               Hrs.                                          Pain                             Pain was Gone              57.  E - 12/7/82                                                                            33 F  Sprained Back                                                                              Lumbo-Sacral         Response Good; Pain             12/8/82       MM. Rt. Side                                                                               Region & Insertion   Diminished First                                                               Day.                            12/9/82       Previous Episode                                                                           of Rt. Lat. Dors.    Back Improved From                            Took 2 wks. to                                                                             MM. Applied 2-3      Each Application                              Heal        times Daily for 3                                                              days                                            58.  E - 12/20/82                                                                           38 M  Lower Back  Sprayed Entire                                                                           10 Min.    10 Min. Pain                                                                   Reduced.                                      Sprain (Lifted                                                                             Lumbo-Sacral         20 Min. Pain Gone                             Garage Door);                                                                              Region of the        and Brace not Needed                          wore a back brace                                                                          back                 When Patient Walked                                                            Out                        59.  E - 12/28/82                                                                           44 M  Lower Back Pain                                                                            Lower Back                                                                               2-3 Min.   Relief Within                   12/29/82                  Over Painful Area    Minutes; Used Over              12/20/82                                       the Period of 4 Days                                                           With Good                  __________________________________________________________________________                                                         Results                     GRADING KEY                                                                    54 E  Excellent, no pain or awareness at all during period                     9 G  Good, relief from pain but an awareness of the area                       5 F  Fair, relief from pain is not as definitive nor as striking as            Excellent or Good                                                              6 N  None, no change                                                           *Propylene carbonate with aspirin (15% solution)                         

In addition, a number of dermatologic conditions have been treated, as reported below in Table II (Tests 60-70 and 74) with propylene carbonate alone and with propylene carbonate in combination with a second therapeutic agent.

Test 73 involved treatment of a specific tooth and gum condition in a manner to demonstrate specifically the potentiating effect of propylene carbonate in combination with penicillin.

                                      TABLE II                                     __________________________________________________________________________     Test                                                                           Patient                                                                             Test                                    Improvement Time                  Number                                                                              Grade                                                                              Age                                                                               Sex                                                                               Condition Treatment  Days Used                                                                               & Degree                          __________________________________________________________________________     60.  E   60 F  Poison Ivy                                                                               PC Application                                                                            July 26 Applied                                                                         Poison Ivy on Arm to Which                       on Both Arms                                                                             to One Arm;                                                                               Several Days                                                                            PC was Applied Cleared up                                  Control Arm Not                                                                           27th & 28th                                                                             Rapidly. Untreated Arm Did                                 Treated             Not Heal. Untreated Arm                                                        Showed                                                                         Discolored Scars; PC                                                           Treated                                                                        Arm no Discoloration, no                                                       Scars                             61.  E   17 M  Acne, Chin &                                                                             P.C.I. (Polypy-                                                                           8/1/82, 7 days                                                                          Pustules Gone in 1 Day;                          Cheeks;   lene Carbonate-     Condomes Reduced in 2 Days;                      Condomes, Iodine, 1000 PPM)   Face Cleared in 5 Days. PCI                      Pustules  Applied 2-3 Times   Continued 1 mo. - Acne                                                         Cleared.                                                   Daily               1 wk. Without Medication -                                                     Acne                                                                           Returned; with Medication,                                                     Face                                                                           Again Cleared Up                  62.  E   67 M  Forehead, Rash                                                                           2 Applications                                                                            8/17, 1 day                                                                             Itch Gone in Several Hours.                      Allergy   PC                  Dermatitis Improved Within                                                     Hours, Even Though it had                                                      Grown Worse for Several                                                        Days                                                                           Prior to Treatment                63.  E   47 F  Poison Ivy                                                                               2 Applications                                                                            8/17, PC 1st Day, PC, Itch Gone                           of Both Legs                                                                             Rt. Leg - PC                                                                              Worked as                                                                               Immediately; Redness Gone                                  Lt. Leg - PCI                                                                             Well as  PCI - Itch Gone                                                                Immediately;                                               (1000 PPM) PCI      Redness Gone 2 Days Follow-                                                    ing; Poison Ivy Dried up on                                                    Both Legs; no                                                                  Discoloration,                                                                 no Scars                          64.  E   21 M  Poison Ivy                                                                               2 Applications                                                                            8/26     1st Day Itch Relieved                            of the Right leg                                                                         Rt. Leg - PC        Immediately; Lesions Dried                                                     up                                                                             and Spreading of Poison ivy                                                    Prevented                         65.  E   35 F  Herpes Simplex                                                                           Initially 2                                                                               9/1 & 9/2                                                                               Herpes Simplex Dried                             I of Lips &                                                                              Applications                                                                              & 9/3    up; Lesions Cleared up;                          Face; Prior                                                     PC; then PC                                                                         3 Days                                                                             Compared to Lidex Which                                                              Treatment With                                                                           for 2 Subse-        Had no Effect                                    Lidex Ineffective                                                                        quent days                                            66.  E   24 F  Acne Vulgaris                                                                            Daily Appli-                                                                              9/4 through                                                                             Improvement Noted                                of Forehead,                                                                             cations for 3                                                                             October, on Second Day of                                 Cheeks & Chin                                                                            Months; Beginning                                                                         November;                                                                               PCI Use; Within                                  Moderate  on 9/4 - PCI                                                                              Used Daily                                                                              One Week, Acne Was                                         (1000 PPM)          Almost Cleared                    67.  E   26 F  Acne Vulgaris                                                                            2 Times    10/14,   Improvement Began in                             Moderate  Daily; PCI November,                                                                               a Few Days and in Two                                      (2000 PPM) December,                                                                               Weeks Cleared Up                                                      1982                                       68.  E   59 M  First Degree                                                                             Only one   11/1/82  Reduced Pain Immediately.                        Burn Rt. Index                                                                           Application         Within 2 Hours, There Were                       Finger    PC                  No Redness, No Swelling,                                                       and No Tenderness -                                                            no evidence of burn at                                                         all                               69.  E   20 F  Herpes Simplex                                                                           2 Applications                                                                            11/8, 11/9                                                                              Herpes Lesions Dried Up                          of Lip - PC                                                                              Daily      & 11/10/82                                                                              First Day. Healed in 2-3                                                       Days                                                                           (By Comparison, Previous                                                       Bouts                                                                          of Herpes Lasted 10 Days to                                                    2 Weeks in this patient)          70.  E   27 F  Acne Vulgaris                                                                            2 Applications                                                                            11/29/82 -                                                                              Cleared Redness in 1 wk.                         Mild Case Daily - PCI                                                                               12/12/82 Papules & Condomes Gone in                                 (2000 PPM)          2 wks. Then Continued Use                                                      as Needed                         71.  E   60 M  First Degree                                                                             Immediate  12/24/82 Pain Stopped Immediately;                        Burn of Thumb                                                                            Application         Redness Diminished. There                                                      was                                                        then 2 times        no Pain and the Formation                                                      of                                                         Within One          Vessicle was Retarded                                      Hour - PC                                             72.  E   20 M  Acne Vulgaris                                                                            P.C.I.     December Marked Improvement                                         (2000 PPM) through  First 7 Days. Then on                                      Applied Daily                                                                             January  Medication for 6 Weeks,                                               After a Test                                                                            Cleared Completely                                                    Period                                                                         7 Days                                     73.  Treatment of Pyorrhea of the gum and abscessed gum and molar tooth        (1)    First treatment - Oral Tetracycline 250 mgm. b.i.d. for 15 days                No improvement of condition                                             (2)    Second treatment - Oral SKF Pen VK 250 mgm. b.i.d. for 10 days                 No improvement of condition                                             (3)    Third treatment - Local topical application b.i.d. of 1/2 Tab. 250             mgm. of SKF VK in aqueous sol.                                                 (dist. H.sub.2 O) for 7 days                                                   No improvement of condition                                             (4)    Fourth Treatment - PC local topical application b.i.d. for 7 days              Reduced suppuration and bleeding                                               Slight improvement - yet condition flared up during two day period             without any medication                                                  (5)    Fifth treatment regime -                                                                   Solution 1/4 of a 250 mgm. tablet of Pen VK in                                 solution with PC applied topically                                             to tooth & gum b.i.d. for 7 days.                                              Suppuration and swelling completely reduced. Only                              slight amount of bleeding remained -                                           no flare up during two day rest period without                                 medication                                                  (6)    Sixth treatment regime -                                                                   a repeat of 2 and 5 in combination, i.e., P.C. & Pen                           VK (1/4 Tab. 250 mgm.) topically                                               b.i.d. plus Pen VK 250 orally b.i.d. for 7 days.                               Abcess healed - no reoccurrence after one month.                               (i.e., December 31, 1982)                                   74.  E   25 F  Infected  Applied 2 Times                                                                           12/24-25-                                                                               First the Ulcers Dried Up                        Ulcerations                                                                              for 3 Days - PC;                                                                          26/82    Then Swelling, Pain, and                         Dorsum Rt.                                                                               Previous Treatment  Redness Diminished; by the                       Foot of 2 wks.                                                                           with A & D Ointment Third Day, Ulcers Were                                                         Dried                                            Duration  and Furacin were to Up and Healed                                              no Avail                                              __________________________________________________________________________

In general, the variety of clinical applications in which propylene carbonate has been tested and found to be useful include: as an anti-inflammatory, an anti-allergenic, a carrier of other therapeutic agents, and as a potentiating agent for other therapeutic agents. The types of co-reactive therapeutic agents with which propylene carbonate has been used include analgesics (e.g., aspirin), antibiotics (e.g., penicillin), and anti-septics (e.g., iodine). Other possible co-reactive medicaments include steroids, cortico-steriods, and anti-histamines.

In addition, the unusual effectiveness (i.e., quick remission) on virus infections and allergic manifestations noted to date suggests that propylene carbonate may have some special effects on histaminic and immunologic systems in the body, thereby, presaging an even wider spectrum of medical applications for this compound.

Among dermatologic and trauma-related conditions which may be treated with propylene carbonate, either alone or in combination with other drugs, are eczemas, burns, lesions, abrasions, incisions, allergies, and infectious disorders such as herpes, scabies, or even psoriatic conditions.

The results of Test 73 indicate that propylene carbonate, in combination with penicillin, is aparently more effective in the treatment of an abscessed tooth and gum (to cause remission of the infectious condition) than either penicillin or propylene carbonate alone. This occurred after the abscess remained resistant to systemic treatment with Tetracycline and SKF Pen VK penicillin. Upon topical application of a solution of propylene carbonate and Pen VK, the abscess showed signs of remission within a week. Upon a second application a week later in conjunction with systemic penicillin treatment, complete remission of the infection resulted.

The results of the other tests reported in Table II may be summarized as follows:

POISON IVY. Upon topical application of propylene carbonate, the poison ivy infected area dried in the same day and was prevented from spreading to other areas. Itching stopped within minutes; the condition healed within a few days without leaving the skin discoloration usually seen as a post-poison ivy condition. This also suggests that propylene carbonate, when applied to other types of lesions of the skin, may accelerate healing and help to minimize scarring.

HERPES SIMPLEX-1 (viral infection). Upon topical application of propylene carbonate to the affected skin area, healing occurred within a few days and did not spread to contiguous areas. Itching stopped immediately and the condition healed within a few days rather than in the usual 7 to 10 days, which occurs without treatment. This suggests the possible efficacy of the use of propylene carbonate in the treatment of the lesions of genital herpes, and the use of propylene carbonate in treating other virus-related conditions.

URTICARIA. Upon the topical application of propylene carbonate to urticaria of the face, the allergic manifestation disappeared within a few hours, apparently acting as an antihistamine.

BURNS. Propylene carbonate was applied topically to first degree burns; pain was immediately relieved, and blistering was prevented. Healing occurred within 2 days.

INFECTED SKIN ULCERATIONS. Upon topical treatment with propylene carbonate the condition healed over a period of 3 days with minimal scarring noted 3 weeks after healing. This condition had been resistant to healing with A & D ointment & Furacin for 2 weeks prior to the use of propylene carbonate.

ACNE VULGARIS (seven cases). By topical application of a solution of 1000 PPM Iodine in propylene carbonate or 2000 PPM Iodine in propylene carbonate, the Acne conditions showed considerable to complete remission. These clinical examples demonstrate the ability of propylene carbonate in combination with a second therapeutic agent, to act as a potentiator as well as a vehicle for that agent.

COMPARATIVE EXAMPLE

The only known medicament listed in the Physicians' Desk Reference (Medical Economics Company, Inc., Oradell, NJ: 1982) which includes propylene carbonate is Lidex Ointment, manufactured and sold by Syntex, Inc. of Palo Alto, CA, the apparent assignee of the above-referenced Chang, Shastri, and Alvarez patents. According to the 1982 Physicians' Desk Reference, and the literature distributed with Lidex Ointment, it is composed of "Fluocinonide 0.5 mg/g, in a specially formulated ointment based consisting of Amerchol Cab (mixture of sterols and higher alcohols), white petrolatum, propylene carbonate, and propylene glycol. It provides the occlusive and emollient effects desirable in an ointment. In these formulations, the active ingredient is totally in solution." It is said to be effective in the relief of inflammatory manifestations of corticosteroid-responsive dermatoses.

For purposes of comparison with the present invention, Lidex Ointment was topically administered to test case #31-A 61 year old female with osteoarthritis of the hands (Test #31 in Table I above). No relief from the pain occurred when Lidex Ointment was applied to her left hand. Simultaneously, propylene carbonate was applied to her right hand resulting in immediate relief from pain. Additionally, when 100% propylene carbonate was applied over the Lidex Ointment on the left hand, no relief from the pain was obtained presumably because propylene carbonate could not penetrate the Lidex Ointment.

Thereafter, this same patient was made the subject of a clinical test of the present invention, with good results as indicated in Test #31b of Table I.

This significantly better result, obtained using the present invention, is considered to be a dramatic demonstration of the efficacy of the present invention. Moreover, this result is in sharp contrast to the result obtained using a composition, apparently typical of the prior art, in which propylene carbonate is present only in a minor amount and in combination with other solvents, vehicles, and medicaments.

While this invention has been described with reference to specific embodiments thereof, the appended claims are intended to be construed to extend not only to these embodiments and forms of the invention but to such other forms and embodiments as may be devised by those skilled in the art, without departing from the true spirit and scope of the invention. 

We claim:
 1. A method of treating pain, infection, trauma, or inflammation in the dermal or sub-dermal tissue of a subject by topical administration to the skin area proximate said tissue of a therapeutically effective amount of a medicament consisting essentially of propylene carbonate.
 2. A method, as recited in claim 1, wherein osteo-arthritis is treated.
 3. The method of claim 1 wherein the pain is from abnormal conditions selected from the group consisting of osteo arthritis and related conditions, injury, trauma, allergenic inflammation, poison ivy, tooth and gum abscess, burns, acne or pyorrhea.
 4. The method of claim 3 wherein the pain is from osteo arthritis and related conditions.
 5. The method of treating pain comprising topical administration to the skin area proximate the pain of a therapeutically effective amount of propylene carbonate. 